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1.
Biomed Pharmacother ; 175: 116738, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38759291

RESUMO

Despite significant advancements in multiple myeloma (MM) treatment in recent years, most patients will eventually develop resistance or experience relapse. Matrine, a primary active compound of traditional Chinese medicinal herb Sophora flavescens Ait, has been found to have anti-tumor properties in various types of malignant tumors. Whether autophagy plays a crucial role in the anti-MM effect of matrine remain unknown. Herein, we found that matrine could trigger apoptosis and cell cycle arrest, and meanwhile induce autophagy in MM cells in vitro. We further ascertained the role of autophagy by using ATG5 siRNA or the autophagy inhibitor spautin-1, which partially reversed matrine's inhibitory effect on MM cells. Conversely, the combination of matrine with the autophagy inducer rapamycin enhanced their anti-tumor activity. These findings suggest that autophagy induced by matrine can lead to cell death in MM cells. Further mechanism investigation revealed that matrine treatment increased the levels of reactive oxygen species (ROS) and AMPKα1 phosphorylation and decreased the phosphorylation of mTOR in MM cells. Additionally, co-treatment with AMPKα1 siRNA or the ROS scavenger N-acetyl-1-cysteine weakened the increase in autophagy that was induced by matrine. Finally, we demonstrated a synergistic inhibitory effect of matrine and rapamycin against MM in a xenograft mouse model. Collectively, our findings provided novel insights into the anti-MM efficacy of matrine and suggest that matrine induces autophagy by triggering ROS/AMPK/mTOR axis in MM cells, and combinatorial treatment of matrine and rapamycin may be a promising therapeutic strategy against MM.


Assuntos
Proteínas Quinases Ativadas por AMP , Alcaloides , Apoptose , Morte Celular Autofágica , Matrinas , Mieloma Múltiplo , Quinolizinas , Espécies Reativas de Oxigênio , Transdução de Sinais , Serina-Treonina Quinases TOR , Quinolizinas/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Mieloma Múltiplo/metabolismo , Alcaloides/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Humanos , Apoptose/efeitos dos fármacos , Animais , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Proteínas Quinases Ativadas por AMP/metabolismo , Morte Celular Autofágica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos , Autofagia/efeitos dos fármacos
2.
Front Immunol ; 15: 1354992, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38736891

RESUMO

CD44 is a ubiquitous leukocyte adhesion molecule involved in cell-cell interaction, cell adhesion, migration, homing and differentiation. CD44 can mediate the interaction between leukemic stem cells and the surrounding extracellular matrix, thereby inducing a cascade of signaling pathways to regulate their various behaviors. In this review, we focus on the impact of CD44s/CD44v as biomarkers in leukemia development and discuss the current research and prospects for CD44-related interventions in clinical application.


Assuntos
Biomarcadores Tumorais , Receptores de Hialuronatos , Leucemia , Células-Tronco Neoplásicas , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/imunologia , Receptores de Hialuronatos/metabolismo , Leucemia/metabolismo , Leucemia/terapia , Leucemia/imunologia , Biomarcadores Tumorais/metabolismo , Animais , Transdução de Sinais , Terapia de Alvo Molecular
4.
J Cell Mol Med ; 27(12): 1682-1696, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37154878

RESUMO

Perturbations in autophagy, apoptosis and differentiation have greatly affected the progression and therapy of acute myeloid leukaemia (AML). The role of X-linked inhibitor of apoptosis (XIAP)-related autophagy remains unclear in AML therapeutics. Here, we found that XIAP was highly expressed and associated with poor overall survival in patients with AML. Furthermore, pharmacologic inhibition of XIAP using birinapant or XIAP knockdown via siRNA impaired the proliferation and clonogenic capacity by inducing autophagy and apoptosis in AML cells. Intriguingly, birinapant-induced cell death was aggravated in combination with ATG5 siRNA or an autophagy inhibitor spautin-1, suggesting that autophagy may be a pro-survival signalling. Spautin-1 further enhanced the ROS level and myeloid differentiation in THP-1 cells treated with birinapant. The mechanism analysis showed that XIAP interacted with MDM2 and p53, and XIAP inhibition notably downregulated p53, substantially increased the AMPKα1 phosphorylation and downregulated the mTOR phosphorylation. Combined treatment using birinapant and chloroquine significantly retarded AML progression in both a subcutaneous xenograft model injected with HEL cells and an orthotopic xenograft model injected intravenously with C1498 cells. Collectively, our data suggested that XIAP inhibition can induce autophagy, apoptosis and differentiation, and combined inhibition of XIAP and autophagy may be a promising therapeutic strategy for AML.


Assuntos
Leucemia Mieloide Aguda , RNA Interferente Pequeno , Proteína Supressora de Tumor p53 , Humanos , Apoptose , Autofagia , Diferenciação Celular , Linhagem Celular Tumoral , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , RNA Interferente Pequeno/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
5.
J Transl Med ; 21(1): 309, 2023 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-37149661

RESUMO

BACKGROUND: The previous studies have revealed that abnormal RNA-binding protein Musashi-2 (MSI2) expression is associated with cancer progression through post-transcriptional mechanisms, however mechanistic details of this regulation in acute myeloid leukemia (AML) still remain unclear. Our study aimed to explore the relationship between microRNA-143 (miR-143) and MSI2 and to clarify their clinical significance, biological function and mechanism. METHODS: Abnormal expression of miR-143 and MSI2 were evaluated in bone marrow samples from AML patients by quantitative real time-PCR. Effects of miR-143 on regulating MSI2 expression were investigated using luciferase reporter assay. Functional roles of MSI2 and miR-143 on AML cell proliferation and migration were determined by CCK-8 assay, colony formation, and transwell assays in vitro and in mouse subcutaneous xenograft and orthotopic transplantation models in vivo. RNA immunoprecipitation, RNA stability measurement and Western blotting were performed to assess the effects of MSI2 on AML. RESULTS: We found that MSI2 was significantly overexpressed in AML and exerted its role of promoting AML cell growth by targeting DLL1 and thereby activating Notch signaling pathway. Moreover, we found that MSI2 bound to Snail1 transcript and inhibited its degradation, which in turn upregulated the expression of matrix metalloproteinases. We also found that MSI2 targeting miR-143 is downregulated in AML. In the AML xenograft mouse model, overexpression of MSI2 recapitulated its leukemia-promoting effects, and overexpression of miR-143 partially attenuated tumor growth and prevented metastasis. Notably, low expression of miR-143, and high expression of MSI2 were associated with poor prognosis in AML patients. CONCLUSIONS: Our data demonstrate that MSI2 exerts its malignant properties via DLL1/Notch1 cascade and the Snail1/MMPs axes in AML, and upregulation of miR-143 may be a potential therapeutic approach for AML.


Assuntos
Leucemia Mieloide Aguda , MicroRNAs , Humanos , Animais , Camundongos , Leucemia Mieloide Aguda/patologia , Genes Supressores de Tumor , Proliferação de Células/genética , Regulação para Cima , Modelos Animais de Doenças , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Receptor Notch1/genética , Receptor Notch1/metabolismo , Proteínas de Ligação a RNA/genética
6.
Transl Cancer Res ; 11(6): 1463-1471, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35836512

RESUMO

Background: The T-cell non-Hodgkin's lymphoma (T-NHL) patients with bone marrow (BM) invasion have a poor prognosis. Although BM biopsy is still a confirmed diagnosis method, the low sensitivity restricts its use to detect the minimal BM invasion. It is of great clinical significance to establish a rapid and highly sensitive method to evaluate BM invasion. Methods: We conducted a retrospective study of 85 patients with new diagnosed T-NHL patients enrolled in our institute. The bone marrow mononuclear cells (BMMNCs) cells were isolated, stained with different combinations of antibody and subjected to flow cytometry analysis. Results: We found that CD3+CD7- T cells increased significantly in the BM in T-NHL patients with BM invasion. The patients were divided into the low and high groups according to the cutoff value of 1.035% obtained by analyzing the receiver operating characteristic (ROC) curve of the percentage of CD3+CD7- T cells of nucleated cells at diagnosis. The ratio of invasion in high group was markedly higher than that in low group. Furthermore, CD3+CD7- T cells presented significantly higher level of programmed cell death-1 (PD-1), lymphocyte-activation-gene-3 (LAG3) and CD4/CD8 ratio. Conclusions: Our study revealed the percentage of CD3+CD7- T cells of nucleated cells in BM was a potential diagnostic predictor of BM invasion with T-NHL.

7.
Front Immunol ; 11: 1710, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849603

RESUMO

Intratumoral accumulation of CD4+CD25+Foxp3+ regulatory T (Treg) cells occurs in acute myeloid leukemia (AML), but little is known about the role of tumor cells themselves in this process. Here, we showed that an immune checkpoint PD-L1 expressed by AML cells promoted the conversion and expansion of Treg cells sustaining high expression of Foxp3 and PD-1 as well as a suppressive function. Furthermore, an AML cell line HEL overexpressed PD-L1 promoted the conversion and expansion of Treg cells and CD4+PD-1+Foxp3+ T (PD-1+Treg) cells from the conventional CD4+ T cells. CD4+CD25highPD-1+ T cells secreted more IL-10 production than CD4+CD25highPD-1- T cells. IL-35, another cytokine secreted by Treg cells, promoted the proliferation of HL-60 cells and enhanced chemoresistance to cytarabine. Blockade of PD-1 signaling using anti-PD-L1 antibody dramatically impaired the generation of Treg cells and sharply retarded the progression of a murine AML model injected with C1498 cells. The frequency of intratumoral PD-1+ Treg cells was capable of predicting patient survival in patients with AML. In conclusion, our data suggest that PD-L1 expression by AML cells may directly drive Treg cell expansion as a mechanism of immune evasion and the frequency of PD-1+ Treg cells is a potential prognostic predictor in patients with AML.


Assuntos
Antígeno B7-H1/imunologia , Leucemia Mieloide Aguda/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem
8.
J Cell Mol Med ; 23(2): 1022-1033, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30411500

RESUMO

Chronic exposure to benzene is known to be associated with haematotoxicity and the development of aplastic anaemia and leukaemia. However, the mechanism underlying benzene-induced haematotoxicity, especially at low concentrations of chronic benzene exposure has not been well-elucidated. Here, we found that increased autophagy and decreased acetylation occurred in bone marrow mononuclear cells (BMMNCs) isolated from patients with chronic benzene exposure. We further showed in vitro that benzene metabolite, hydroquinone (HQ) could directly induce autophagy without apoptosis in BMMNCs and CD34+ cells. This was mediated by reduction in acetylation of autophagy components through inhibiting the activity of acetyltransferase, p300. Furthermore, elevation of p300 expression by Momordica Antiviral Protein 30 Kd (MAP30) or chloroquine reduced HQ-induced autophagy. We further demonstrated that in vivo, MAP30 and chloroquine reversed benzene-induced autophagy and haematotoxicity in a mouse model. Taken together, these findings highlight increased autophagy as a novel mechanism for benzene-induced haematotoxicity and provide potential strategies to reverse this process for therapeutic benefits.


Assuntos
Acetilação/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzeno/farmacologia , Doenças Hematológicas/induzido quimicamente , Adulto , Animais , Antígenos CD34/metabolismo , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Cloroquina/farmacologia , Feminino , Doenças Hematológicas/metabolismo , Humanos , Hidroquinonas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Modelos Animais , Adulto Jovem
9.
Front Immunol ; 9: 2227, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319662

RESUMO

CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in bone marrow microenvironment in acute myeloid leukemia (AML). However, little is known about how the tumor environment including tumor cells themselves affects this process. Here we demonstrated that AML cells expressed inducible T-cell costimulator ligand (ICOSL) that can provide costimulation through ICOS for the conversion and expansion of Tregs sustaining high Foxp3 and CD25 expression as well as a suppressive function. TNF-a stimulation up-regulated the expression of ICOSL. Furthermore, both the conversion and expansion of CD4+CD25+Foxp3+ T cells and CD4+ICOS+Foxp3+ T cells were induced by co-culture with AML cells overexpressed ICOSL. CD4+CD25+ICOS+ T cells possessed stronger ability to secrete IL-10 than CD4+CD25+ICOS- T cells. The mechanism by which IL-10 promoted the proliferation of AML cells was dependent on the activation of the Akt, Erk1/2, p38, and Stat3 signaling pathways. Blockade of ICOS signaling using anti-ICOSL antibody impaired the generation of Tregs and retarded the progression of an AML mice model injected with C1498 cells. The expression of ICOSL of patient AML cells and ICOS+ Tregs were found to be predictors for overall survival and disease-free survival in patients with AML, with ICOS+ Treg cell subset being a stronger predictor than total Tregs. These results suggest that ICOSL expression by AML cells may directly drive Treg expansion as a mechanism of immune evasion and ICOS+ Treg cell frequency is a better prognostic predictor in patients with AML.


Assuntos
Regulação Neoplásica da Expressão Gênica/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Leucemia Mieloide Aguda/imunologia , Linfócitos T Reguladores/imunologia , Evasão Tumoral/imunologia , Adolescente , Adulto , Animais , Biópsia , Medula Óssea/patologia , Linhagem Celular Tumoral/transplante , Proliferação de Células , Modelos Animais de Doenças , Intervalo Livre de Doença , Feminino , Humanos , Ligante Coestimulador de Linfócitos T Induzíveis/antagonistas & inibidores , Ligante Coestimulador de Linfócitos T Induzíveis/imunologia , Interleucina-10/imunologia , Interleucina-10/metabolismo , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Cultura Primária de Células , Prognóstico , Linfócitos T Reguladores/metabolismo , Microambiente Tumoral/imunologia , Adulto Jovem
10.
J Cell Mol Med ; 22(12): 5955-5963, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30247801

RESUMO

Accumulating evidence shows that tigecycline, a first-in-class glycylcycline, has potential antitumour properties. Here, we found that tigecycline dramatically inhibited the proliferation of multiple myeloma (MM) cell lines RPMI-8226, NCI-H929 and U266 in a dose and time-dependent manner. Meanwhile, tigecycline also potently impaired the colony formation of these three cell lines. Mechanism analysis found that tigecycline led to cell cycle arrest at G0/G1 with down-regulation of p21, CDK2 and cyclin D1, rather than induced apoptosis, in MM cells. Importantly, we found that tigecycline induced autophagy and an autophagy inhibitor bafilomycin A1 further amplified the tigecycline-induced cytotoxicity, suggesting that autophagy plays a cytoprotective role in tigecycline-treated MM cells. Mechanisms modulating autophagy found that tigecycline enhanced the phosphorylation of AMPK, but did not decrease the phosphorylation of Akt, to inhibit the phosphorylation of mTOR and its two downstream effectors p70S6K1 and 4E-BP1. Tigecycline effectively inhibited tumour growth in the xenograft tumour model of RPMI-8226 cells. Autophagy also occurred in tigecycline-treated tumour xenograft, and autophagy inhibitor chloroquine and tigecycline had a synergistic effect against MM cells in vivo. Thus, our results suggest that tigecycline may be a promising candidate in the treatment of MM.


Assuntos
Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Tigeciclina/uso terapêutico , Adenilato Quinase/metabolismo , Animais , Antineoplásicos/farmacologia , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cloroquina/farmacologia , Citoproteção/efeitos dos fármacos , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Mieloma Múltiplo/ultraestrutura , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Toxicol In Vitro ; 46: 361-369, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28886972

RESUMO

The Akt/glycogen synthase kinase-3ß (GSK-3ß)/ß-catenin signaling pathway has been shown to play an important role in hematopoiesis, and hematopoietic cells are sensitive targets for benzene-induced hematotoxicity. We therefore hypothesized that dysregulation of the Akt/GSK-3ß/ß-catenin signaling was associated with benzene-induced hematotoxicity. Here, we showed that hydroquinone (HQ), a major metabolite of benzene in humans, significantly inhibited cell viability and colony formation while inducing apoptosis of human bone marrow mononuclear cells in vitro. Interestingly, we found that HQ inhibited the Akt affected ß-catenin signaling by activation of GSK-3ß, resulting in downregulation of ß-catenin and its targets Cyclin D1 and Survivin. HQ blocked nuclear translocation of ß-catenin and lymphoid enhancer-binding factor 1 (LEF-1), and importantly, HQ also reduced the interaction of ß-catenin and LEF-1 in the nucleus. As expected, blockage of GSK-3ß activity with a GSK-3ß inhibitor lithium chloride (LiCl) or activation of Akt signaling with an Akt agonist insulin-like growth factor-1 (IGF-1) could inhibit HQ-induced activation of GSK-3ß as well as hematotoxicity. Taken together, our results suggest that HQ-induced hematotoxicity in bone marrow mononuclear cells is associated with dysregulation of Akt/GSK-3ß/ß-catenin signaling due to the dissociation of ß-catenin/LEF-1 complex, and LiCl and IGF-1 may be two potential agents to ameliorate HQ-induced hematotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Benzeno/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Hidroquinonas/toxicidade , Leucócitos Mononucleares/efeitos dos fármacos , beta Catenina/metabolismo , Adolescente , Adulto , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Hidroquinonas/metabolismo , Pessoa de Meia-Idade , Fosforilação , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
12.
PeerJ ; 5: e4139, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29302387

RESUMO

BACKGROUND: Pretreatment platelet count has been reported as a potential tool to predict survival outcome in several solid tumors. However, the predictive value of pretreatment platelet count remains obscure in de novo acute myeloid leukemia (AML) excluding acute promyelocytic leukemia (M3). METHODS: We conducted a retrospective review of 209 patients with de novo non-M3 AML in our institute over a period of 8 years (2007-2015). Receiver operating characteristic (ROC) curve analysis was used to determine the optimal platelet (PLT) cutoff in patients. We analyzed the overall survival (OS) and disease free survival (DFS) using the log-rank test and Cox regression analysis. RESULTS: By defining the platelet count 50 × 109/L and 120 × 109/L as two cut-off points, we categorized the patients into three groups: low (<50 × 109/L), medium (50-120 × 109/L) and high (>120 × 109/L). On univariate analysis, patients with medium platelet count had longer OS and DFS than those with low or high platelet count. However, the multivariate analysis showed that only longer DFS was observed in patients with medium platelet count than those with low or high platelet count. CONCLUSION: Our findings indicate that pretreatment platelet count has a predictive value for the prognosis of patients with non-M3 AML.

13.
J Cell Mol Med ; 21(6): 1171-1181, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28026112

RESUMO

Pharmacological modulation of autophagy has been referred to as a promising therapeutic strategy for cancer. Matrine, a main alkaloid extracted from Sophora flavescens Ait, has antitumour activity against acute myelocytic leukaemia (AML). Whether autophagy is involved in antileukaemia activity of matrine remains unobvious. In this study, we demonstrated that matrine inhibited cell viability and colony formation via inducing apoptosis and autophagy in AML cell lines HL-60, THP-1 and C1498 as well as primary AML cells. Matrine promoted caspase-3 and PARP cleavage dose-dependently. Matrine up-regulated the level of LC3-II and down-regulated the level of SQSTM1/p62 in a dose-dependent way, indicating that autophagy should be implicated in anti-AML effect of matrine. Furthermore, the autophagy inhibitor bafilomycin A1 relieved the cytotoxicity of matrine by blocking the autophagic flux, while the autophagy promoter rapamycin enhanced the cytotoxicity of matrine. Additionally, matrine inhibited the phosphorylation of Akt, mTOR and their downstream substrates p70S6K and 4EBP1, which led to the occurrence of autophagy. In vivo study demonstrated that autophagy was involved in antileukaemia effect of matrine in C57BL/6 mice bearing murine AML cell line C1498, and the survival curves showed that mice did benefit from treatment with matrine. Collectively, our findings indicate that matrine exerts antitumour effect through apoptosis and autophagy, and the latter one might be a potential therapeutic strategy for AML.


Assuntos
Alcaloides/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética , Quinolizinas/administração & dosagem , Serina-Treonina Quinases TOR/genética , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Matrinas
14.
J Transl Med ; 14(1): 132, 2016 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-27176825

RESUMO

BACKGROUND: Immune regulation is crucial for the pathogenesis of B-cell acute lymphoblastic leukemia (B-ALL). It has been reported that Th17 cells as a newly identified subset of CD4(+) T cells are involved in the pathogenesis of several hematological disorders. However, the role of Th17 cells in the pathophysiology of B-ALL is still unclear. METHODS: The frequencies of T cells were determined by flow cytometry in the peripheral blood and bone marrow of 44 newly diagnosed B-ALL patients and 25 age-matched healthy donors. The cell viability and apoptosis were determined by CCK-8 assay and Annexin V staining, respectively. Western blot was applied to identify the level of Akt and Stat3 phosphorylation. RESULTS: We assessed and observed a significantly increased frequency of Th17 cells and a drastically decreased frequency of Th1 cells in peripheral blood mononuclear cells and bone marrow mononuclear cells from newly diagnosed B-ALL patients compared with healthy donors. Furthermore, increased levels of Th17-related cytokines including IL-17, IL-21, IL-23, IL-1ß, and IL-6 were presented in between blood and marrow in B-ALL patients. Both IL-17A and IL-21, two Th17-secreted cytokines, induced the proliferation of B-ALL cell line Nalm-6 and patient B-ALL cells isolated from B-ALL patients, herein either cytokine led to the phosphorylation of Akt and Stat3. Additionally, IL-17A promoted resistance to daunorubicin via activation of Akt signaling and the PI3K/Akt inhibitor LY294002 or perifosine almost completely rescued daunorubicin-induced cell death in B-ALL cells. CONCLUSIONS: Our findings suggest that elevated Th17 cells secrete IL-17A by which promotes the proliferation and resistance to daunorubicin in B-ALL cells through activation of Akt signaling. Th17 cells may represent a novel target to improve B-ALL immunotherapy.


Assuntos
Daunorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interleucina-17/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Th17/imunologia , Adolescente , Adulto , Idoso , Proliferação de Células/efeitos dos fármacos , Separação Celular , Ativação Enzimática/efeitos dos fármacos , Humanos , Interleucinas/metabolismo , Pessoa de Meia-Idade , Fator de Transcrição STAT3/metabolismo , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Adulto Jovem
15.
PLoS One ; 11(4): e0153330, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27058040

RESUMO

Dysfunction of histone acetylation inhibits topoisomerase IIα (Topo IIα), which is implicated in benzene-induced hematotoxicity in patients with chronic benzene exposure. Whether histone deacetylase (HDAC) inhibitors can relieve benzene-induced hematotoxicity remains unclear. Here we showed that hydroquinone, a main metabolite of benzene, increased the HDAC activity, decreased the Topo IIα expression and induced apoptosis in human bone marrow mononuclear cells in vitro, and treatment with two HDAC inhibitors, namely trichostatin A (TSA) or a mixture of ribosome-inactivating proteins MCP30, almost completely reversed these effects. We further established a benzene poisoning murine model by inhaling benzene vapor in a container and found that benzene poisoning decreased the expression and activity of Topo IIα, and impaired acetylation of histone H4 and H3. The analysis of regulatory factors of Topo IIα promoter found that benzene poisoning decreased the mRNA levels of SP1 and C-MYB, and increased the mRNA level of SP3. Both TSA and MCP30 significantly enhanced the acetylation of histone H3 and H4 in Topo IIα promoter and increased the expression and activity of Topo IIα in benzene poisoning mice, which contributed to relieve the symptoms of hematotoxicity. Thus, treatment with HDAC inhibitors represents an attractive approach to reduce benzene-induced hematotoxicity.


Assuntos
Antígenos de Neoplasias/metabolismo , Benzeno/toxicidade , Ciclopropanos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Acetilação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Masculino , Camundongos , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/metabolismo
16.
Oncol Rep ; 35(6): 3705-13, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27035419

RESUMO

Momordica anti-human immunodeficiency virus protein of 30 kDa (MAP30) has been shown to exhibit potent antitumor activities against several solid tumors. In the present investigation we demonstrated that MAP30 significantly inhibited the proliferation of acute myeloid leukemia (AML) HL-60 and THP-1 cell lines and patient AML cells through autophagy inhibition and apoptosis induction. Intriguingly, MAP30-induced cell death and apoptosis were partially rescued in combination with an autophagy activator rapamycin, and aggravated in combination with an autophagy inhibitor bafilomycin A1 in HL-60 cells, suggesting that autophagy is a pro-survival signal and its inhibition contributes to the induction of apoptosis in MAP30­induced cell death. Further mechanism analysis demonstrated that MAP30 enhanced p300, and C646, a selective inhibitor of p300, markedly promoted autophagy and partially rescued the MAP30-induced cell death in HL-60 cells and patient AML cells. Collectively, our findings suggest that apoptosis and autophagy act cooperatively to elicit MAP30-induced cell death and MAP30 may be a potential antitumor drug candidate against AML.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leucemia Mieloide Aguda/patologia , Proteínas Inativadoras de Ribossomos Tipo 2/farmacologia , Benzoatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HL-60 , Humanos , Macrolídeos/farmacologia , Momordica charantia/metabolismo , Nitrobenzenos , Extratos Vegetais/farmacologia , Pirazóis/farmacologia , Pirazolonas , Sirolimo/farmacologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores
17.
Neuroreport ; 27(5): 301-5, 2016 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-26836463

RESUMO

Uric acid (UA), the final product of purine metabolism, has been reported to be reduced in patients with various neurological disorders and is considered to be a possible indicator for monitoring the disability and progression of multiple sclerosis. However, it remains unclear whether there is a close relationship between UA and myasthenia gravis (MG), or whether UA is primarily deficient or secondarily reduced because of its peroxynitrite scavenging activity. We investigated the correlation between serum UA levels and the clinical characteristics of MG. We assessed 338 serum UA levels obtained in 135 patients with MG, 47 patients with multiple sclerosis, and 156 healthy controls. In addition, we compared serum UA levels when MG patients were stratified according to disease activity and classifications performed by the Myasthenia Gravis Foundation of America, age of onset, duration, and thymus histology (by means of MRI or computed tomography). MG patients had significantly lower serum UA levels than the controls (P<0.001). Moreover, UA levels in patients with MG were inversely correlated with disease activity and disease progression (P=0.013). However, UA levels did not correlate significantly with disease duration, age of onset, and thymus histology. Our findings suggest that serum level of UA was reduced in patients with MG and serum UA might be considered a surrogate biomarker of MG disability and progression.


Assuntos
Miastenia Gravis/sangue , Ácido Úrico/sangue , Adulto , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino
18.
PLoS One ; 10(8): e0136484, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26308531

RESUMO

RNA-binding protein Musashi-2 (Msi2) is known to play a critical role in leukemogenesis and contributes to poor clinical prognosis in acute myeloid leukemia (AML). However, the effect of Msi2 silencing on treatment for AML still remains poorly understood. In this study, we used lentivirus-mediated RNA interference targeting Msi2 to investigate the resulting changes in cellular processes and the underlying mechanisms in AML cell lines as well as primary AML cells isolated from AML patients. We found that Msi2 was highly expressed in AML cells, and its depletion inhibited Ki-67 expression and resulted in decreased in vitro and in vivo proliferation. Msi2 silencing induced cell cycle arrest in G0/G1 phase, with decreased Cyclin D1 and increased p21 expression. Msi2 silencing induced apoptosis through down-regulation of Bcl-2 expression and up-regulation of Bax expression. Suppression of Akt, Erk1/2 and p38 phosphorylation also contributed to apoptosis mediated by Msi2 silencing. Finally, Msi2 silencing in AML cells also enhanced their chemosensitivity to daunorubicin. Conclusively, our data suggest that Msi2 is a promising target for gene therapy to optimize conventional chemotherapeutics in AML treatment.


Assuntos
Daunorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Leucemia Mieloide Aguda/patologia , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/antagonistas & inibidores , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas de Ligação a RNA/genética , Células Tumorais Cultivadas
19.
IIE Trans Healthc Syst Eng ; 5(4): 238-254, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-29541376

RESUMO

Parkinson's disease (PD) is the second most common neurological disorder after Alzheimer's disease. Key clinical features of PD are motor-related and are typically assessed by healthcare providers based on qualitative visual inspection of a patient's movement/gait/posture. More advanced diagnostic techniques such as computed tomography scans that measure brain function, can be cost prohibitive and may expose patients to radiation and other harmful effects. To mitigate these challenges, and open a pathway to remote patient-physician assessment, the authors of this work propose a data mining driven methodology that uses low cost, non-invasive sensors to model and predict the presence (or lack therefore) of PD movement abnormalities and model clinical subtypes. The study presented here evaluates the discriminative ability of non-invasive hardware and data mining algorithms to classify PD cases and controls. A 10-fold cross validation approach is used to compare several data mining algorithms in order to determine that which provides the most consistent results when varying the subject gait data. Next, the predictive accuracy of the data mining model is quantified by testing it against unseen data captured from a test pool of subjects. The proposed methodology demonstrates the feasibility of using non-invasive, low cost, hardware and data mining models to monitor the progression of gait features outside of the traditional healthcare facility, which may ultimately lead to earlier diagnosis of emerging neurological diseases.

20.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 22(5): 1235-8, 2014 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-25338564

RESUMO

This study was aimed to detect the expression of Musashi-2 (Msi2) in acute myeloid leukemia (AML) and investigate the relationship between Msi2 and other clinical parameters, especially CD34. A total RNA was extracted from bone marrow of newly diagnosed AML patietns. The Msi2 mRNA expression in newly diagnosed AML patients was detected with real-time fluorescence quantitative RT-PCR. The expression level of CD34 in above-menthioned patients was detected by flow cytometry (FCM). The relationship between the expression of Msi2 mRNA and clinical outcome in AML patients was analysed. The results showed that (1)the expression of Msi2 mRNA in newly diagnosed AML patients was much higher than that in healthy volunteers (P < 0.05) , especially in M1, M4 and M5 patients; (2)the expression level of Msi2 did not correlate with age, sex, white blood cell count of peripheral blood, AML1/ETO and PML/RARa fusion gene (P > 0.05); (3) Msi2 expression level in patients with CD34(+) cells was significantly higher than that in patients with CD34(-) cells (P < 0.05). It is concluded that the Msi2 mRNA expresses in leukamia stem cells, the high expression of Msi2 mRNA has been found in newly diagnosed AML patients, especially in M1, M4 and M5 patients, the high expression also has been observed in patients with CD34(+).


Assuntos
Leucemia Mieloide Aguda/genética , Células-Tronco Neoplásicas , Proteínas de Ligação a RNA/genética , Citometria de Fluxo , Regulação Leucêmica da Expressão Gênica , Humanos , Células-Tronco Neoplásicas/metabolismo , RNA Mensageiro
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